The Atlantic Coast Sexually Transmitted Infection Cooperative Research Center (AC

描述(由申请人提供)：拟议的大西洋海岸(AC)STI CRC是一个高度整合的、多学科的联盟，由经验丰富的研究人员组成，他们致力于推动淋球菌(Ng)、沙眼衣原体(Ct)和Ng/CT感染领域的基础科学和翻译科学的发展，这将加深我们对这些性传播感染的发病机制的理解，并导致新干预措施的开发。为了实现这些目标，我们将解决以下四个具体方案目标。目的一是从Ng介导的免疫抑制机制以及Ng和Ct逃避或与天然防御效应器相互作用的机制来确定Ng和Ng/Ct混合感染的免疫生物学。将描述两种干扰树突状细胞(DC)功能的新的Ng免疫抑制途径。这些Ng通路影响宿主对衣原体的反应的假设也将得到检验。将使用单一和双重感染的小鼠模型进行阴道蛋白质组分析，以确定可能限制或增强感染的新效应物，并评估生殖激素对宿主因子表达的影响。我们还将在细胞水平和实验性小鼠感染过程中，研究穿孔素-2在Ng、Ct和Ng/衣原体细胞内生物学中的作用。目的二是建立组织培养系统、改进的动物模型和免疫学系统，以研究Ng/CT配方，并加速产品开发。旨在通过两种不同途径促进Ng侵袭的组织培养系统和先进的显微镜将被用于研究Ng/Ct混合感染细胞的细胞内生物学。将使用人类转铁蛋白补充的小鼠建立改进的小鼠模型，这些小鼠是人类癌胚抗原相关细胞黏附分子(hCEACAM-1)的转基因小鼠；这些模型将用于识别可以区分单一感染和双重感染的潜在生物标记物。为了便于研究混合感染的免疫生物学，将建立体外、体外和体内检测方法，以检测Ng对人类免疫功能的影响 DC导向的抗CM反应。目的3是了解耐药淋病传播的遗传基础。将测试头孢曲松耐药决定因素对体外和体内微生物适合性的影响，并将检测恢复适合性的补偿性突变。 已确认身份。目标4是开发一种淋病疫苗和有效治疗淋病和衣原体感染的新疗法。将开发一种有前景的Ng Tf受体疫苗，并将评估先前存在的衣原体感染对该疫苗效果的影响。铁螯合剂将作为一种营养疗法进行测试，一种组蛋白脱乙酰酶抑制剂的原型将作为一种潜在有效的表观遗传疗法进行测试，该疗法可以诱导天然效应物的表达，并抑制病原体诱导的炎症。

DESCRIPTION (provided by applicant): The proposed Atlantic Coast (AC) STI CRC is a highly integrated, multidisciplined alliance of experienced investigators who are committed to advancing basic and translational science in the area of Neisseria gonorrhoeae (Ng), Chlamydia trachomatis (Ct) and Ng/Ct infections that will further our understanding of the pathogenesis of these sexually transmitted infections and lead to the development of new interventions. To meet these goals, we will address the following four programmatic specific aims. Aim 1 is to define the immunobiology of Ng and Ng/Ct co-infection with respect to mechanisms of Ng-mediated immunosuppression and the mechanisms by which Ng and Ct evade or interact with effectors of the innate defense. Two novel Ng immunosuppressive pathways that interfere with dendritic cell (DC) function will be characterized. The hypothesis that these Ng pathways affect host responses to Chlamydia will also be tested. A vaginal proteome analysis will be performed using mouse models of single and dual infection to identify novel effectors that may limit or enhance infection and to assess the influence of reproductive hormones on the expression of host factors. We will also investigate the role of perforin-2, a membrane-bound pore-forming effector, in the intracellular biology of Ng, Ct and Ng/Chlamydia at the cellular level and during experimental murine infection. Aim 2 is to develop tissue culture systems, improved animal models, and immunological systems for studying Ng/Ct confection and to accelerate product development. Tissue culture systems designed to promote Ng invasion through two distinct pathways and sophisticated microscopy will be utilized to examine the intracellular biology of Ng/Ct coinfected cells. Improved mouse models will be established using human transferrin-supplemented mice that are transgenic for the human carcinoembryonic antigen-related cellular adherence molecule (hCEACAM-1); these models will be used to identify potential biomarkers that can discriminate single and dual infections. To facilitate studies on the immunobiology of co-infection, in vitro, ex vivo and in vivo assays will be developed to examine the effect of Ng on DC-directed anti-Cm responses. Aim 3 is to understand the genetic basis of the spread of antibiotic resistant gonorrhea. The effect of ceftriaxone resistance determinants on microbial fitness in vitro and in vivo will be tested and compensatory mutations that restore fitness will be identified. Aim 4 is to develop a gonorrhea vaccine and novel therapies effective against both gonorrhea and Chlamydia infections. A promising Ng Tf receptor vaccine will be developed and the effect of a pre-existing Chlamydia infection on the efficacy of this vaccine will be assessed. Iron-chelators will be tested as a nutritional therapy and a prototype histone deacetylase inhibitor will be tested as a potentially effective epigenetic therapy that induces the expression f innate effectors and suppresses pathogen-induced inflammation.